Transfusion registry network for genetically characterized blood products

ABSTRACT

Disclosed is a registry system, including member institutions, in which transfusion donors and recipients are registered following genotyping, which would typically take place in a member institution, or a member institution would have access to the genotyping information, if performed outside. The registry database can be accessed and searched by members seeking samples of particular type(s). Systems are disclosed for maintaining economic viability of genotyping in connection with transfusions, by maximizing the number of units placed with the minimal number of candidate donors typed. Genotyping of potential donors, and product supply, is matched to forecasted demand. Genotyping can also be limited to the more clinically relevant markers. The registry system can also be integrated with one format of assay which generates an image for analysis, whereby the imaged results can be analyzed and redacted by experts in a central location, and then transmitted back to the patient or their representative.

RELATED APPLICATIONS

This application claims priority to U.S. application Ser. No.11/092,420, filed Mar. 29, 2005, which claims priority to U.S.Provisional Application Ser. Nos. 60/586,931 and 60/621,196. Priority toall these applications is hereby claimed.

BACKGROUND

The prevailing paradigm of organizing the supply of blood unitsavailable for transfusion relies on routine typing of transfusionantigens by hemagglutination. Typically, the major transfusion antigengroups, namely A, B, O and D, are typed at collection while a select setof minor group antigens such as RhCE, Kell and Kidd are typed only asneeded For blood group antigens other than ABO and D, source material isdiminishing, and the cost of FDA-approved commercial reagents isescalating. Many antibodies used for testing for minor blood groupantigens (especially when searching for an absence of a high prevalenceantigen) are not FDA-approved and are characterized to varying degreesby those who use them. In addition, some antibodies are limited involume, weakly reactive, or not available. Collectively, thelabor-intensive approach limits the number of donors one can test:thereby restricting the supply of antigen-negative RBC products forpatients who have produced the corresponding alloantibody, and, morerecently, restricting the supply of Rh and K matched RBCs for patientsin the Stroke Prevention Trial (STOP) program, which was designed toprevent immunization of such patients.

Recipients exposed to foreign transfusion antigens generally will formantibodies directed against those antigens. Allo-immunized patients, asubpopulation comprising approximately 2% of transfused patients, and upto 38% of multiply transfused patients, require red blood cell productswhich do not contain the offending antigen. Such units typically must befound either in the limited available supply or must be found, in realtime, by serological typing of such likely candidate units as may beavailable in inventory. The selection of candidate units for “stat”typing, performed in immunohematology laboratories, is guided largely byempirical factors. The delay introduced by the search for matching unitscan exacerbate emergency situations and generally will incur substantialcost to hospitals and/or insurance carriers by delaying in-hospitalstay. More generally, allo-immunization to red blood cell antigens whichare also displayed on other cells (see Table I) and recognized bycertain pathogens such as malaria, can introduce unnecessary healthrisks whose elimination would improve the general health.

The procurement of matched blood to recipients who either display anuncommon antigen or lack a common antigen, is particularly problematic.While such incidences are considered “rare,” occurring at a rate of onein 1,000 recipients, the supply of matched units is very limited. Thus,existing national collections of special units, including the AmericanRare Donor Program (ARDP), register donors encountered in theimmunohematology laboratories of its members: only 30,000 donors havebeen registered (see, e.g., the Red Cross Website). In comparison, theNational Maarow Donor Program (NMDP), a national registry of prospectivebone marrow donors who have been genotyped for polymorphisms in certainloci of the Human Leukocyte Antigen (HLA) gene complex, in the year2000, comprised 2.7 million fully characterized and 4.1 million knowndonors to supply matching bone marrow transplants for only ˜2,400transplantations per year. See the National Marrow Donor ProgramWebsite.

Distribution of the precious few special units available in the programalso leaves substantial room for improvement. At present, relyingprimarily on telephone contacts, only 1,000 special units are placed peryear, while up to 2% of the approximately 4-5 million recipients ofblood transfusions per year, that is 100,000 recipients, would benefitfrom improved availability.

In view of this situation, a method of providing a large and diverseinventory of fully typed blood units, and a method of instant andefficient distribution of units in response to requests posted to acentral registry would be desirable in order to improve the publichealth and to minimize the cost accruing in the health care system inthe form of unnecessarily prolonged hospital stays, adverse transfusionreactions (see Hillyer et al., Blood Banking and Transfusion Medicine;published. by Churchill Livingston, Philadelphia Pa.) and otherpotential complications arising from allo-immunization.

However, absent substantial government or private funding for such anendeavor, a registry of “critical mass” must be created and operated ina commercially viable manner. The ARDP operation, representative ofcurrent practice, illustrates the difficulty: In order to identify aspecial donor, up to 1,000 donors may have been typed, and from acollection of 30,000 such special units, only 1,000 were placed. Whilespecial units fetch a higher price than do “vanilla” red blood cellproducts, the premium does not come close to covering the cost, in viewof the substantial amount of excess typing required. Commercialviability, under these conditions, is doubtful.

SUMMARY

Described is the efficient organization and operation of a diverseregistry of fully characterized blood units. Preferably, donors arecharacterized by DNA typing of the clinically most relevant geneticmarkers, including a set of mutations of Human Erythrocyte Antigens(HEA) including genetic variants of Rh, and additional antigens such asHLA and HPA. The registry, also referred to as a Transfusion Network,comprising certain application programs and databases preferablyaccessible via a web-browser interface, offers essentially instantaccess to linked inventories of typed units of donor blood (“actual”units) as well as access to genotyped donors who are available on-call(“callable” units), along with requisite information relating to donorstatus, inventories of actual units or information relating to callableunits ran be held by subscribing member organizations, who also mayparticipate in the operation and governance of the registry.

In a preferred embodiment, the registry network comprises an alliance ofdominant regional and national donor centers (such as New York BloodCenter and United Blood Services) which would set new standards intransfusion medicine. In another embodiment, regional donor centers andtransfusion services are linked so as to create the critical mass ofregional centers (both domestic and foreign) to decentralize the marketby competing with the dominant national donor centers.

An “actively managed” registry—Existing registries such a the ARDPlargely operate as passive repositories of donors encountered per chanceduring blood drives. Registries of bone marrow donors operated by theNMDP or comparable organizations around the world (REF), while in somecases actively funding bone marrow drives, operate in essentially thesame manner of underwriting the large-scale typing of volunteer donorsand collecting results. TO the extent that the population of donors andpopulation of recipients are not balanced, this approach generally willbe very inefficient from the point of view of maximizing the probabilityof a matching a recipient request.

To overcome this inefficiency and to ensure commercial viability, apreferred strategy is described herein for constructing and maintaininga registry of genotyped donors which maximizes the number of unitsplaced with the minimal number of candidate donors typed. To this end,relevant parameters relating to managing supply and forecasting demandare identified, and methods are described to optimize these parametersso as to maximize revenue and minimize total cost. The registry performsreal-time analysis of supply and demand balance and directs itssubscribing members to balance their respective donor typing operations.

A transfusion network, operated as an active registry, permitsnear-instant selection of prospective donors matching a given recipientby way of implementation on a global network such as the world wide web,thereby also facilitating the efficient distribution of units ininventory, further supported by transaction management including orderplacement and delivery. The registry will generate revenue fromsubscription as well as transaction fees, offering a set of products andservices as described herein. Thus, a commercially viable registry, thefirst such in transfusion medicine, is disclosed, to improve clinicaloutcomes while enhancing economic efficiency.

In one embodiment, large-scale, rapid and cost-effective DNA typing,also herein referred as genotyping, of prospective donors is performedto permit instant matching of registered donors to recipients of knownphenotype or genotype in a manner improving the clinical outcome oftransfusion while improving economic efficiencies. To the extent thatgenotyped donors are retained, the cost of typing is minimized, asdiscussed herein.

The registry server preferably executes a “genetic cross-matching, gXM”algorithm to identify actual and callable donors within the registry, AgXM algorithm relating to a selection of the clinically most relevanthuman erythrocyte antigen (HEA) mutations is described in a co-pendingapplication (see Provisional Application No. 60/621,196, entitled “AMethod of Genetic Cross-Matching of Transfusion Recipients to RegisteredDonors,” as well as applications to be filed claiming priority to it,all of which are incorporated by reference).

DESCRIPTION OF THE FIGURES

FIG. 1 is an illustration of a transfusion registry network linkingmultiple donor centers offering blood-derived products to multiplehospitals requesting blood-derived products for transfusion to patients.Participating parties can perform donor genotyping, patient genotypingand patient antibody screening (using, e.g., BeadChip™ assay kits). Theregistry performs genetic cross-matching and can offer a variety ofadditional products and services.

FIGS. 2A to 2D is a graphical depiction of the central components andsubsystems of a BeadChip™ format for multiplexed analysis ofpolymorphisms and profiling of antibodies enabling the large-scalegenotyping of donors and patients, as well as detection andidentification of antibodies circulating in patient serum.

FIG. 3 is a graphical depiction of a uniform interface for presentationof data to the registry, preferably by way of a web-enabled AutomatedAllele Analysis (AAA) program (as disclosed in U.S. application Ser. No.10/909,638, incorporated by reference), and the connection of theregistry to linked inventories

FIG. 4 is a graph showing the dependence of cost and revenue projectionsfor a multiple donation scenario for various values of the repeatprobability, RHO.

FIG. 5 is an illustration of the concept of optimal resolution(described in text).

DETAILED DESCRIPTION

In order to maximize the economic efficiency of the transfusionregistry, it will be preferable to adopt a strategy of minimizing thetotal number of donors typed for every recipient request fulfilled. Thefollowing exposition refers to a genotype to represent a combination ofmarker alleles, where, for each marker, the possible values of theallele are Normal (1), Homozygous (−1) or Heterozygous (0), and aspecific genotype, representing a combination of alleles, thus has theform of a ternary string.

Estimating Demand Requests for Special Units—In order to maintain aregistry of candidate donors such that the maximal number of requestsfrom prospective recipients for special units can in fact be matchedwhile the number of excess donors typed is kept to a minimum, it will becritical to construct an estimate of anticipated demand.

Denote by:

-   -   N^(R) the number of requests anticipated (or received);    -   8 the probability of receiving (logging) a request for a        specific genotype;    -   : the probability of matching a request (to a pre-determined        level of resolution)        Available evidence indicates that the incidence of certain        genotypes varies substantially between ethnic groups (see G.        Hashmi et al., “A Flexible Array Format for Large-scale, Rapid        Blood Group DNA Typing,” Transfusion, in press). Therefore, the        probability of a request for blood from a donor of specific        genotype received from a random sample of a heterogeneous        pan-ethnic population in fact represents a weighted average of        probabilities, 8_(s), for each of multiple constituent        homogeneous subpopulations. The population-specific        probabilities may be cast in the form:

8_(s)˜(N^((Rs))/N^((R)))f^((s))Σ(r)

where f^((s)) represents the frequency of occurrence of a certainallele, the ratio (N^((Rs))/N^((R))) represents the relative proportionof individuals in subpopulation s within the pan-ethnic population atlarge, and Σ(r) represents a function of excess risk associated with aspecific subpopulation (relative to the population at large). Thefunction Σ(r), which may assume positive or negative values, reflectsactuarial probabilities which in turn reflect genetic risk, e.g., thehigher than average incidence of sickle cell anemia inAfrican-Americans, or higher than average incidence of kidney disease incertain native American Indian tribes, requiring multiple transfusions,and environmental risk, e.g., the lower probability of, e.g., the Amishto suffer trauma in automobile accidents.

The probability, :, of matching a specific request depends on thediversity of the registry and its linked inventories of actual andcallable donors.

Managing Supply Selection of Donors from Stratified Populations—inaccordance with the preferred strategy of registry operation, the supplyof registered donors will be adjusted to balance the anticipated demand.

Denote by:

-   -   N the number of new donors tested;    -   , the fraction of special units encountered in a test        population; 0≦, <1;    -   Φ the fraction of special units sold.

The probability, Φ, of selling any specific unit is determined, forgiven unit price, by the probability. :, of matching a request for sucha unit. Provided that an acceptable price for a unit is agreed upon,then:

Φ=:

Preferably, the strategy for balancing the supply of registered donorswill reflect the increased probability of finding an acceptable matchfor a prospective recipient of transfusion within a donor population ofsimilar heritage. The similarity of genotype among individuals ofsimilar heritage has been established for a variety of genetic markerssuch as those for certain inherited genetic disorders, includingso-called Ashkenazi Jewish Diseases and Cystic Fibrosis (see the JewishVirtual Library Website), as well as for the highly variable humanleukocyte gene complex which encodes for the human leukocyte antigens(HLA) determining the compatibility of recipients and donors of solidorgans and bone marrow through the National Marrow Donor Programwebsite. For blood group genotypes, but one example is provided by thehigh incidence in individuals of South Chinese heritage of theMiltenberger mutation within the MNS blood group (see M. Reid, “TheBlood Group Antigen FactsBook” (2003)) which is largely absent inindividuals of Caucasian heritage.

As with demand estimation, the probability of encountering a specificgenotype in a pan-ethnic and hence genetically heterogeneous donorpopulation will reflect the existence of constituent homogeneoussubpopulations displaying varying values of that probability:

,=(N ⁽¹⁾ /N)f ⁽¹⁾+(N ⁽²⁾ /N)f ⁽²⁾+ . . . +(N ^((s)) /N)f ^((s))

where, as before, f⁽¹⁾, f⁽²⁾ . . . , f^((s)) denote allele frequencies.To balance the supply of registered donors to anticipated demand, itwill be desirable to select, for each subpopulation, s, shared amongdonor and recipient populations, the number of registered donors inaccordance with the condition:

(N ^((s)) /N)=C(N ^((Rs)) /N ^((R)))Σ(r)

The constant, C, captures factors such as the anticipated number ofunits required per recipient. This condition dictates that the registry,rather then genotyping alt corners, would accept only a certaincontinent of donors from each subpopulation.

Factors determining Profitability—A key aspect of operating atransfusion registry network with an acceptable profit margin concernsthe pricing for a test permitting the genotyping a donor sample for adesignated number of genetic markers, preferably by invokingelongation-mediated Multiplexed analysis of polymorphisms (“eMAP”; asdisclosed in U.S. application Ser. No. 10/271,602, incorporated byreference).

Denote by:

N_(k) the number of new donors tested in year k, where k=0, 1, 2, . . ., n;

R_(k) the number of repeat donors (from year k−1) in year k=1, 2 . . .n;

Δ the fraction of repeat donors; generally R_(k)<N_(k), and thus Δ<1.

Δ_(S) the fraction of repeat donors among special donors; Δ_(S)<1.

, the fraction of special units encountered in a test population; 0≦,<1;

c the cost of typing one sample;

Φ the fraction of special units sold;

s the excess revenue (over the “vanilla” unit) of a special unit ofproduct.

The cost of screening in year k is: C_(k)=cN_(k)−g(R_(k), R_(k-1), . . .), that is, in any year but the first (k=0), the total cost of typingN_(k) donor samples will be reduced by a certain portion reflecting thenumber of repeat donors from previous years. Variousassumptions—manifesting themselves in specific forms of the functiong(R_(k), R_(k-1), . . . )—are possible. To the cost of typing must beadded the cost of operating the registry—including transaction costs.

The revenue in year k reflects the sale of special units accumulated ininventory, that is: S_(k)=h(N_(k), N_(k-1), . . . ). Variousassumptions—manifesting themselves in specific forms of the functionh(N_(k), N_(k-1), . . . )—are possible.

The profit in year k is given by P_(k)=S_(k)−C_(k). Break-even, P_(k)=0,is attained at a certain k.

EXAMPLE 1 Single Repeat Donations

Assume that a certain constant total number of donors, say N₀, isscreened every year, and that a (constant) fraction of donors repeat,but repeat only once, namely in the year following their initialdonation. Then R_(k)=ΔN_(k-1), and:

Yr0 Yr1 Yr2 New donors N₀ N₁ = N₀ − R₁ N₂ = N₀ − R₂ Repeat donors R₁ =ΔN₀ R₂ = ΔN₁where R₂=ΔN₁=Δ(N₀−R₁)=ΔN₀−Δ²N₀ and N₂=N₀−ΔN₀+Δ²N₀=N₀(1−Δ+Δ²).Generalizing, one finds the expression for N_(k) to be N_(k)=N₀(1−Δ+Δ²−Δ³+ . . . ); the alternating series reflects the fact that, asrepeat donors stay away, a greater number of new donors must be screenedin every even year. For n sufficiently large so that Δ^(2n)<<1, thisexpression turns out to be N_(k)=N₀/(1+Δ), independent of n; forexample, with Δ=½, Δ^(2n)=(½)^(2n)= 1/256 for n=4.

Assume further that revenue in any given year reflects the sale of acertain fraction, Φ, of the total units, , N₀, available that year, atan excess sales price, s, per sample, and that the population of repeatdonors within the special population equals that within the generalpopulation. Then

Yr0 Yr1 Yr2 S₀ = Φ(,N₀)s S₁ = Φ(,N₀)s S₂ = Φ(,N₀)sThen P_(n)=S_(n)−C_(n)=[,Φs−c/(1+Δ)]N₀, independent of n. Under theseassumptions, to attain break-even, P_(n)=0, or c/s=(1+Δ),Φ, the cost perunit screened must not exceed a certain fraction of the excess revenuein each year.

For example, with reported numbers of Δ=½ (see Schreiber, G. B. et al.,“Targeting Repeat Blood Donors Can Increase Supply,” Transfusion 43:591-97 (2003)),=0.001 (percentage of “rare” units in pan-ethnicpopulation) and Φ=⅕, reflecting the placement of 1,000 “rare” units(from a stock of 30,000), with approximately 5,000 new rare unitsacquired per year (See the National Marrow Donor Program website), oneobtains c/s= 3/2*0.001*⅕=0.0003. Since s will likely not exceed $1,000,the price per test will have to be negligibly small, not a scenario fora profitable large-scale screening operation. In fact, this is near theworst case scenario in which, along with the low abundance of specialsamples, and low percentage of placement, donors do not repeat (Δ=0).

It is anticipated that proper demand projection and inventorymanagement, combined with providing instant access to such inventoriesby way of a transfusion registry network, as disclosed herein, willprovide a basis to attain an operating regime of ,→0.1 and Φ→1 so that,even with Δ=½, c/s= 3/2*0.1*1=0.15.

EXAMPLE 2 Multiple Repeat Donations

In contrast to the previous Example 1, assume that of the total numberof donors, say N₀, screened in the first year, a (constant) fraction ofdonors, once recruited, repeat every year. Given that each donor isgenotyped only once, this will have a cumulative effect on costreduction.

To illustrate the effect, assume first that the same fraction of generaldonors and special donors repeat, that is: Δ=Δ_(S), and that thisfraction is constant.

Yr0 Yr1 Yr2 Cost C₀ = cN₀ C₁ = c(N₀ − R₁) C₂ = c(N₀ − R₂ − R₁) = cN₀(1 −Δ) = cN₀(1 − Δ)² Revenue S₀ = Φ(,N₀)s S₁ = Φ(,N₀)s S₂ = Φ(,N₀)sThen P_(n)=S_(n)−C_(n)=[,Φs−c(1−Δ)^(n)]N₀. The contrast to the model ofExample 1 is dramatic: the requisite cost of typing required to attainthe same revenue, decreases geometrically with n, the slope of thedecrease being set by Δ. Break-even corresponds to c/s=,Φ/(1−Δ)^(n), andprofit grows rapidly thereafter.

FIG. 4 illustrates the evolution of projected cost and excess revenuefor different values of the repeat probability, Δ. Precedents forrelatively high repeat probabilities exist, especially in donors who areaware of their special status. It will be desirable to provideincentives to such donors, as described below.

Mutually Beneficial Interaction of Registry and ReagentManufacturer—Provided that the large-scale genotyping of donors andpatients is enabled by an efficient methodology, preferably invoking theeMAP-HEA design in conjunction with the BeadChip™ format (US ProvisionalApplication Ser. No. 60/586,931, entitled “Encoded Probe Pairs forMolecular Blood Group Antigen Molecular Typing and Identification of NewAlleles” and applications claiming priority thereto (incorporated byreference); G. Hashmi et al., “A Flexible Array Format for Large-scale,Rapid Blood Group DNA Typing,” Transfusion, in press; see also: FIG. 2),the cost of genotyping is reduced by the use of the multiplexed formatof analysis and delivery of the assay in a parallel processing format,thereby permitting automation and uniform data management for a largemenu of applications, including the typing of multiple antigen groups(FIG. 3).

In the initial stage, while building its initial donor reservoir, theregistry, to the extent that it bears the cost of recruiting andgenotyping donors, either directly, or indirectly, by way of subscribingmember donor centers, will operate at a loss (FIG. 4). It will bebeneficial for the registry to partner with a reagent manufacturer whowould underwrite the operations in the initial stage, for example byproviding kits at reduced or at no cost to the registry. To the extentthat the registry is successful in retaining special donors and hencereduces its cost of typing, the market opportunity for the reagentmanufacturer declines. To compensate the reagent manufacturer, theregistry could, for example, grant the manufacturer participation in ajointly controlled entity along with a profit sharing arrangement.

EXAMPLE 3 Expanding Fire Registry

The scenario of Example 2 offers several modes of operation. Forexample, the registry might operate in a “non-profit” regime by settingthe ratio c_(n)/s_(n) so as to ensure P_(n)=0. That is, the diagnosticreagent manufacturer, in return for obtaining a designated share ofprofits after break-even, can subsidize the initial ramp-up of theregistry by accepting a lower price per test, corresponding to thecondition P_(n)(c_(n)/s_(n))=0.

Alternatively, the registry, having attained breakeven, may decide toexpand operations by expanding the number of donors screened per year,for example, such that the number of new donors is set by the availableprofit. This provides a mechanism to compensate the participatingreagent manufacturer for the declining sales of tests arising from thesuccessful retention of repeat donors.

Recruiting and Retaining Special Donors—The single repeat and multiplerepeat scenarios indicate the critical role of the effect of the repeatprobability on the profitability of the registry.

As with the recruitment of HLA donors for national registries,genotyping of blood group antigens will permit the identification ofprospective future donors—that is, donors who do not have to donateblood until called upon. For example, analysis of DNA extracted frombuccal swabs would enable “self-collection” in targeted communities suchas churches and synagogues, and simple submission processes, e.g. bymail, to a designated member laboratory (not necessarily a donorcenter), for DNA analysis. This aspect not only allows the extension ofthe universe of known special donors, but also would be invaluable inregistry management, in order to match the volume of donor typing toprojected demand within individual subpopulations.

To refine this model toward a “best case” scenario, retention effortswould be directed to special donors, not the general donor population.The total number of special donors in each designated subpopulationwould be matched to demand projections, as described above. Specialdonors would be given incentive to repeat by granting them, and donatingfamily members, authorized direct emergency access to the registry.

Clinical Benefit vs. Cost of Genotyping “Optimal” Panel Size—Theclinical outcome of transfusion generally would improve with increasingresolution, that is, with the number of genetic markers included in thedetermination of patient and donor genotypes. The greatest benefit wouldderive from matching alleles encoding the clinically most significantblood group antigens (see M. Reid “The Blood Group Antigen FactsBook”(2003)), and the incremental benefit of matching additional alleleswould decrease. Ignoring cost, a reasonable criterion for thedetermining the optimal resolution would be to select this point ofdiminishing incremental benefit.

However, significant economic considerations also apply. Thus, thehigher the degree of resolution required for genetic cross-matching of adonor genotype to that of a patient, the higher the risk to the registryof not being able to place that unit, and the higher the cost of typingthat unit. That is, c, the cost of genotyping, generally will increasewith the number, m, of genetic markers included in the set, while theprobability, , of matching a request and selling a specific unit willdecrease. For example, denoting by f_(First), f_(Second), f_(Third), . .. f_(Last) the relative allele frequencies of markers included incross-matching, in the order of decreasing clinical significance,:˜f_(First)×f_(Second)×f_(Third, . . . ×f) _(Last), thus :˜1/m^(x),where x denotes an exponent, while c˜c₀+a*m^(y), where c₀ denotes aconstant, namely the initial cost of genotyping the first marker, adenotes a constant related to the marginal cost of genotyping additionalmarkers, and y denotes an exponent reflecting the rate of increase incost: for example, using a single-marker method of genotyping such asRestriction Fragment Length Polymorphism (RFLP) or Allele-specific PCR,one would anticipate cost to increase linearly, y=1, while using thepreferred embodiment of elongation-mediated multiplexed analysis ofpolymorphisms (eMAP), one would anticipate cost to increase in asublinear form, y<1. In either case, from the cost-benefit point ofview, there exists an “optimal” resolution. Unless the market wouldcompensate the registry for the higher cost of matching a donor unit tohigh resolution, in which case clinical benefit will set the optimalresolution, m*, that value otherwise will be determined by theintersection of the two functions :=:(m) and c=c(m), as illustrated inFIG. 5.

Implementation of Registry—A co-pending application (U.S. applicationSer. No. 10/909,638, incorporated by reference) discloses algorithms andimplementations for automated allele analysis, and these methods areuseful in connection with genetic cross-matching (gXM) generally, asdisclosed in a further co-pending application (Provisional ApplicationNo. 60/621,196, noted above, incorporated by reference).

Using standard software engineering technologies such as MicroSoft.net(“dot-net”), these methods can be implemented in a manner permittingtheir use in an application-server modality using a standard web browsersuch as Microsoft Explorer™. Preferably, such an implementation, wAAA™,will invoke an SQL server and provide a uniform interface to ArrayImaging Systems generating data for a variety of applications such asmultiplex HEA, HLA and HPA analysis as well as patient and donorantibody identification. As disclosed in a Co-pending application (Ser.No. 10/714,203), data records will be uploaded—preferably usingtransaction protocols preserving donor and patient anonymity—to the wAAAapplication on a central server permitting review and redaction by, anddelivery to authorized users.

Establishing an Efficient Market: Management of Real-timeTransactions—Disclosed is a mode of operating a commercially viableregistry in the form a real-time transaction network offering instantaccess to a diverse collection of characterized donors, that is, bothactual donor-derived blood products in linked inventories, and callablecandidate donors of desirable genotype. Such a registry will increasedemand by extending its reach to a global base of potential customers byproviding access to it products and services by way of a standard webbrowser and permitting applications, notably automated allele analysis,gXM and selection of candidate donors to be performed automatically, inreal time. By offering instant transactions, under a variety of pricingarrangements including contracts, notably futures contracts, as well asreal-time pricing, for example by way of bid-ask matching (currentlyavailable in the context of web-auctions as well as ElectronicCommunications Networks (ECNs) such as InstiNet (http://www.island.com),the registry will create an efficient market for the global procurementand distribution of matched donor units.

Collection of Samples, Assay Performance, Analysis of Assay Results,Patient Counseling and Reporting Results to Patients—Also disclosedherein is a model of implementing molecular diagnostics in a mode of“virtual centralization” which permits the steps of actually performingassays, preferably in a standard and universal format such as the RandomEncoded Array Detection (READ™) format, and the steps of analyzing,interpreting and reporting assay results including communicatingoutcomes to the patient or referring physician, to be performed indifferent locations, such that experts or groups of experts have access,by way of a standard web browser to the wAAA environment to review datagenerated in a location different from their own physical location.

Virtual centralization of the data is accomplished by uploading of datarelating to assay results, and interpretation/analysis thereof, to aserver or other accessible database. It can then be accessed by orsecurely transmitted to authorized parties to perform additionalinterpretation or analysis, or to view or report the results. Useridentification can be secured at all stages of the process so as topreserve confidentiality, such that, for example, only the patient andperhaps his physician will be aware of the patient identity associatedwith particular results.

This model is particularly well-suited to the analysis andinterpretation of results produced by genetic tests, including, resultswhich can be processed for initial analysis by the web-based AAA program(discussed above) or where these results are in the form of images forwhich standard formats of network transmission now exist. Assay formatsproducing suitable images invoke, for example, spatially encoded “dotblot” or “reverse dot blot” formats, including “spotted” probe orprotein arrays; arrays of oligonucleotide probes synthesized in-situ ona substrate, or probes (or proteins) associated with encoded beads: seeU.S. Pat. No. 6,797,524; U.S. application Ser. No. 10/204,799, filed onAug. 23, 2002 “Multianalyte Molecular Analysis UsingApplication-Specific Random Particle Arrays,” (incorporated byreference.

Networking allows the different parties involved in different steps ofthe process to perform their respective functions such as collectingsamples, performing the assay, or analyzing the results, at the samelocation, or at different locations. Performing separate functions bydifferent parties at different locations can provide a significantadvantage in terms of cost and speed of analysis, as parties do not needto travel to a location to carry out their function. It also allowsbetter control over the confidentiality of the results, as results donot need to be physically transported, by non-secure means, to differentlocations.

After sample collection, or self-collection by the patient (e.g., byusing a buccal swab), an assay on a patient sample can be performed at afirst location. The initial assay results, which may be encoded (seeU.S. Pat. No. 6,797,524; US Application Ser. No. 10/204,799, filed onAug. 23, 2002 “Multianalyte Molecular Analysis UsingApplication-Specific Random Particle Arrays,” both being incorporatedherein by reference) or in the form of an assay image (see “Analysis,Secure Access to and Transmission of Array Images,” Ser. No. 10/714,203,filed Nov. 14, 2003, incorporated herein by reference), can be uploadedto a server or transmitted to an analysis site (which may be the sitewhich sold the assay kit to the remote location). The identity of thepatient can be associated with the sample, using, e.g., methods setforth in the co-pending application “Genetic Analysis andAuthentication,” Ser. No. 10/238,439 (incorporated herein by reference).The analysis site decodes or interprets or performs a preliminaryanalysis of the results (and/or the assay image), and may also obtainassistance in interpretation from experts or consultants, who may eitherbe on-site or may transmit an image from the assay, or who have accessto the server with such images or results. The analyzed results can thenbe accessed by, or transmitted to, the patient's physician, or thepatient, or the laboratory where the assay was conducted, which in turnprovides them to the patient's physician and/or the patient. It ispossible to keep the patient identity separated from the results at allstages, so that only the physician and the patient, or even only thepatient, can correlate results with a particular patient. This securesthe confidentiality of assay information, as is desirable in the case ofgenetic information, given the growing concern over maintainingconfidentiality of individual's genetic data.

In this manner, the “front-end” of laboratory practice is standardized,preferably by adoption of a BeadChip™ format of performing multiplexednucleic acid and protein analysis while the “back end”, generallyrequiring specialized expertise, is moved to a network, preferably byimplementation of an application service which provides networkprotocols to transmit assay results, perform analysis, authorize accessto databases for review and result certification, and managecommunication between multiple participants in the process.

It should be understood that the terms and expressions herein areexemplary only, and not limiting, and that the invention is defined onlyin the claims which follow, and includes all equivalents of the claimedsubject matter.

1. A method for operating a registry offering access to genotypedprospective transfusion donors, for matching to a transfusion recipientof given genotype or phenotype, in a manner increasing the probabilityof having an acceptable donor for any recipient querying the registry,over said probability where donors are not stratified and typed as setforth below, while reducing the total number of prospective donors to begenotyped over the number required to be genotyped where donors are notstratified and typed as set forth below, comprising: stratifyingprospective donors and recipients into subpopulations; and for eachsubpopulation, genotyping sufficient numbers of donors of differentgenotypes or phenotypes to fulfill anticipated demand from recipients ofparticular genotypes or phenotypes.
 2. The method of claim 1 whereinblood units are collected from donors of different genotypes orphenotypes to fulfill anticipated demand for blood units from recipientsof particular genotypes or phenotypes.
 3. The method of claim 2 whereinthe registry includes several member institutions, and the inventoriesof the member institutions include genotyped blood units and genotypeddonors who agreed to be available to donate.
 4. The method of claim 1wherein following genotyping of the number of donors anticipated to berequired to match a preset fraction of the anticipated demand fromrecipients, additional donors are not genotyped.
 5. The method of claim1 wherein genetic markers likely to be present in a subpopulation andindicative of a clinically significant adverse event, if mismatchedbetween donor and recipients, are genotyped.
 6. The method of claim 1further including providing incentives to retain donors havingparticular genotypes.
 7. The method of claim 6 wherein said incentivesinclude extending authorization to said donors having particulargenotypes for preferential access, as against other recipients, to theregistry in the event said donors require transfusion.
 8. A method forreducing clinically significant adverse clinical events in transfusionrecipients to less than the number said events encountered if not usingthe method herein, comprising ranking the genetic markers which arerelated to clinically significant events in order of their clinicalsignificance, matching donors and recipients for only those markerswhich are associated with a clinical significance greater than athreshold value, and providing donors with transfusions from matchedrecipients.
 9. The method of claim 8 wherein donors and recipients arenot genotyped for other markers.
 10. A method for reducing clinicallysignificant adverse clinical events in transfusion recipients to lessthan the number of said events encountered if not using the methodherein, comprising: stratifying prospective donors and recipients intosubpopulations; determining, in each subpopulation, genetic markerswhich are associated with clinically significant adverse events;matching donors and recipients for those markers which have a clinicalsignificance greater than a threshold; and providing donors withtransfusions from matched recipients.
 11. The method of claim 10 whereindonors and recipients are not genotyped for markers with a significancebelow the threshold. 12-13. (canceled)
 14. The method of claim 10wherein the genetic markers include RhCE, Kidd, Kell, Duffy, Dombrock,MNS, and combinations of markers of RhCE, Kidd, Kell, Duffy, Dombrockand MNS. 15-16. (canceled)
 17. A method of centralization of moleculardiagnostics within a network of member institutions, comprising:providing to each member institution an assay delivery system capable ofuploading assay data to a central server in a standardized format;providing, through or on said central server, automated analysis andinterpretation of uploaded data to generate preliminary assay results;providing, through or on said central server, access to and expertreview of said preliminary assay results, whereby, following saidreview, final assay results are generated, which are suitable forrelease to patients or their representatives.
 18. The method of claim 17wherein the communication of preliminary and final assay resultsmaintains patient anonymity.
 19. A method of increasing the fraction ofrepeat donations above that experienced when not using the followingmethod by incentivizing selected genotyped donors, wherein saidincentives include extending authorization to said donors havingparticular genotypes for preferential access, as against otherrecipients, to the registry in the event said donors requiretransfusion, and providing transfusions to said genotyped donorsrequiring transfusion.